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Preparation and evaluation of amphiphilic macromolecules-based conjugates and micelles for anticancer drug delivery
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Text
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Title
Preparation and evaluation of amphiphilic macromolecules-based conjugates and micelles for anticancer drug delivery
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NonSort
Identifier
ETD_1625
Identifier
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051195
Language
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eng
Genre
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theses
Subject
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(authority = RUETD)
Topic
Chemistry and Chemical Biology
Subject
(ID = SBJ-2);
(authority = ETD-LCSH)
Topic
Drug delivery systems
Abstract
Micelles assembled from amphiphilic macromolecules (AM) or drug-conjugated AMs were evaluated as anticancer drug carriers in terms of drug content,
sustained/controlled drug release and cytotoxicity of encapsulated/bound drug. Physical drug encapsulation was compared with chemical drug conjugation. The AM micelles were compared with known polymeric delivery systems, Pluronic P85 and Cremophor EL. Generally, AM micelles encapsulated drugs as efficiently (or better) than the established polymeric carriers.
Encapsulated hydrophobic drugs in AM micelles showed non-aggregation of drug and sustained drug release after lyophilization and resolubilization in aqueous solutions; indicating good solution and storage stability of drug-loaded AM micelles. Compared to the polymeric controls, the AM micelles showed faster resolubilization times and better pH/temperature micellar stability.
Cellular entry of AM micelles in human umbilical vein endothelial cells was observed to be endocytotic, observed from the colocalization of fluorescein-labeled AMs and fluorescent dye-stained endosomes or lysosomes that were detected by confocal scanning
microscopy.
Doxorubicin (DOX) was conjugated to AMs via acidic pH-sensitive hydrazone linkers and the DOX-AM micelles had ~ 30 nm sizes. DOX-AMs showed higher drug release at lysosomal pH 5.0 as compared to physiological pH 7.4. Cell proliferation assays of DOX-AM micelles showed better cytotoxicity compared to DOX-loaded AM micelles and free DOX against human hepatocellular carcinoma cells.
As another example of drug conjugation, camptothecin (CPT) was conjugated to AMs via glycine linkers. CPT-AM micelles showed CPT lactone stabilization, higher CPT solubilization, and increased stability against human serum albumin (HSA) on CPT release in vitro. However, cell proliferation assays on the CPT-AM micelles showed comparable cytotoxicity to CPT-loaded AM micelles against human colorectal carcinoma cells.
The placement of CPT conjugation was evaluated by CPT conjugation via mucic acid and functionalized alkyl chains. Carbodiimides were used to conjugate CPT to AM mucic acid, whereas click chemistry conjugated alkyne-terminated CPT to azideterminated AM chains. Higher CPT conjugation was achieved via the functionalized chain ends (i.e. click chemistry) compared to the mucic acid (carbodiimide coupling).
However, lesser HSA impact on CPT in vitro release was observed in CPT attached to the mucic acid.
Overall, the AM-based micelles showed good characteristics as anticancer drug carriers.
sustained/controlled drug release and cytotoxicity of encapsulated/bound drug. Physical drug encapsulation was compared with chemical drug conjugation. The AM micelles were compared with known polymeric delivery systems, Pluronic P85 and Cremophor EL. Generally, AM micelles encapsulated drugs as efficiently (or better) than the established polymeric carriers.
Encapsulated hydrophobic drugs in AM micelles showed non-aggregation of drug and sustained drug release after lyophilization and resolubilization in aqueous solutions; indicating good solution and storage stability of drug-loaded AM micelles. Compared to the polymeric controls, the AM micelles showed faster resolubilization times and better pH/temperature micellar stability.
Cellular entry of AM micelles in human umbilical vein endothelial cells was observed to be endocytotic, observed from the colocalization of fluorescein-labeled AMs and fluorescent dye-stained endosomes or lysosomes that were detected by confocal scanning
microscopy.
Doxorubicin (DOX) was conjugated to AMs via acidic pH-sensitive hydrazone linkers and the DOX-AM micelles had ~ 30 nm sizes. DOX-AMs showed higher drug release at lysosomal pH 5.0 as compared to physiological pH 7.4. Cell proliferation assays of DOX-AM micelles showed better cytotoxicity compared to DOX-loaded AM micelles and free DOX against human hepatocellular carcinoma cells.
As another example of drug conjugation, camptothecin (CPT) was conjugated to AMs via glycine linkers. CPT-AM micelles showed CPT lactone stabilization, higher CPT solubilization, and increased stability against human serum albumin (HSA) on CPT release in vitro. However, cell proliferation assays on the CPT-AM micelles showed comparable cytotoxicity to CPT-loaded AM micelles against human colorectal carcinoma cells.
The placement of CPT conjugation was evaluated by CPT conjugation via mucic acid and functionalized alkyl chains. Carbodiimides were used to conjugate CPT to AM mucic acid, whereas click chemistry conjugated alkyne-terminated CPT to azideterminated AM chains. Higher CPT conjugation was achieved via the functionalized chain ends (i.e. click chemistry) compared to the mucic acid (carbodiimide coupling).
However, lesser HSA impact on CPT in vitro release was observed in CPT attached to the mucic acid.
Overall, the AM-based micelles showed good characteristics as anticancer drug carriers.
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electronic resource
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xvii, 147 p. : ill.
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Ph.D.
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Includes bibliographical references
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by Leilani Singson del Rosario
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del Rosario
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Leilani Singson
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Leilani Singson del Rosario
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Uhrich
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Kathryn
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chair
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Advisory Committee
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Kathryn E Uhrich
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Taylor
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John
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John Taylor
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Warmuth
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Ralf
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Ralf Warmuth
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Barth
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Advisory Committee
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Rutgers University
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Graduate School - New Brunswick
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2009
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2009-05
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xx
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NjNbRU
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Rutgers University Electronic Theses and Dissertations
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ETD
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Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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doi:10.7282/T3ZK5GW0
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ETD doctoral
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The author owns the copyright to this work.
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Open
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Non-exclusive ETD license
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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